This invention pertains to diuretics, particularly to diuretics that are used during surgery or severe trauma under general anesthesia.
This is the United States national stage of International Application PCT/US97/03439, filed Mar. 5, 1997; which claims the priority of the filing date of the United States patent application Ser. No. 08/615,531, filed Mar. 11, 1996, now converted to provisional application Ser. No. 60/040,272.
During surgery or severe trauma, gaseous (volatile) general anesthetics such as isoflurane, enflurane, desflurane, nitrous oxide, halothane, ethylene, cyclopropane, sevoflurane and methoxyflurane cause an undesirable side effect on the kidneys: the use of gaseous general anesthetics during the stress of surgery or severe trauma causes acute renal failure and the nearly complete shutdown of urine production. There are profound and sustained reductions in urine output (antidiuresis), urinary sodium excretion (antinatriuresis), and urinary potassium excretion (antikaluresis). When renal function is thus impaired, the kidneys do not produce normal amounts of urine. Water then accumulates in the vascular and interstitial compartments of the body, leading to fluid overload and electrolyte imbalance. In a healthy surgical patient with normal cardiovascular function, the fluid retention and electrolyte imbalance do not necessarily present complications. But potentially life-threatening complications can develop if the same amount of fluid is retained, or if the same electrolyte imbalance occurs in a surgical patient with a preexisting cardiovascular or renal condition, such as hypertension, angina, hepatic cirrhosis, congestive heart failure, renal failure, myocardial infarction, or arrhythmia. Potentially life-threatening conditions that can develop during or after surgery under general anesthesia include pulmonary edema, seizures, angina, myocardial infarction, cardiac arrhythmia, heart failure, renal failure, renal tubular necrosis, sepsis, gastrointestinal hemorrhage, and central nervous system edema or dysfunction.
Drugs that function as diuretics in conscious patients often do not function at all, or do not function in the same manner when used during general anesthesia. There are a few drugs that have been used to increase urine output and to try to protect the kidneys from damage during anesthesia and surgery, but the existing drugs have complications. Drugs that have been used as diuretics during major operations and treatments for severe trauma include the following: high ceiling loop diuretics such as furosemide, bumetanide, and ethacrynic acid: mannitol, an osmotic diuretic; dopamine, a dopaminergic agonist; and clonidine, an alpha-2 adrenoceptor agonist. These drugs have significant limitations in that either they have a limited ability to increase urine output during anesthesia and surgery, or they cause excessive loss of water and electrolytes. Moreover, in surgical patients with a reduced kidney perfusion pressure (e.g. patients with a preexisting renal disease, or patients suffering from shock or hypotension), these drugs are largely ineffective as diuretics. In cases where these agents do produce a diuretic response during anesthesia and surgery, the level of water output can be exceedingly high. In addition, these agents can cause adverse, potentially life-threatening electrolyte imbalances such as hyponatremia (low plasma sodium) or hyperkalemia (high plasma potassium). Disturbances of electrolyte concentration during the peri- or post-operative periods can severely impair cerebral, neuromuscular, respiratory, and cardiac function. The likelihood that an electrolyte imbalance will cause cardiovascular and renal complications greatly increases in elderly patients, patients with a reduced cardiovascular or renal reserve, and patients being treated with certain other drugs such as cardiac glycosides, corticosteroids, amphotericin B, or other diuretics.
Furosemide, bumetanide and ethacrynic acid are short acting loop diuretics (none of which are opioid agonists). Furosemide is currently one of the drugs most frequently selected for increasing urine output during surgery under general anesthesia. Furosemide has been used to treat fluid overload and hypertension in the following settings: (1) following renal transplant, (2) as an adjunct in reducing intracranial pressure in patients undergoing surgery for intracranial hematomas, (3) for the treatment of edema associated with renal failure, and (4) as an adjunct in treating acute pulmonary edema. Furosemide is administered during a surgical procedure, but not before. Adverse effects related to fluid or electrolyte disturbances can include hyperglycemia, hyperuricemia, hypokalemia, hyponatremia, hypovolemia, hypochloremic alkalosis, tachycardia, oliguria (diminished output of urine), and arrhythmias. Furosemide can also cause acute hypotensive episodes during rapid diuresis that can then lead to further impairment of renal function. Moreover, furosemide can cause excessive losses of water, sodium, potassium, and calcium that can lead to life-threatening complications as severe as those caused by renal shutdown. For example, the marked rise in urine output caused by furosemide can cause renal failure by inducing hypovolemia (abnormally decreased volume of circulating blood). Hypovolemia is a particular problem in patients who are only minimally euvolemic (normal blood volume).
Y. Hamaya et al., xe2x80x9cDiuretic Effect of Clonidine during Isoflurane, Nitrous Oxide, and Oxygen Anesthesia,xe2x80x9d Anesthesiology, vol. 81, pp. 811-819 (1994) discussed the diuretic effect of clonidine (not an opioid agonist) during general anesthesia and surgery in human patients. When clonidine was administered 90 minutes before anesthesia it caused significant diuresis during surgery, but also produced substantial losses of sodium and potassium. Clonidine also produced a substantial decrease in mean arterial pressure and heart rate in these patients. Further, clonidine can alter the pharmacological action of other drugs that are frequently co-administered during various surgical operations. For example, the heart rate response to intravenous administration of atropine is attenuated. Moreover, the pressor response to intravenous ephedrine is augmented by clonidine pretreatment.
Mannitol (not an opioid agonist) is extensively employed as an osmotic diuretic. Mannitol is sometimes used to decrease intracranial pressure and fluid volume. Mannitol has also been used for prophylaxis and the treatment of acute renal failure during cardiovascular operations and in treating severe traumatic injury. However, mannitol causes extracellular (e.g., intravascular and interstitial) volume expansion, and it can precipitate congestive heart failure and pulmonary edema in patients with limited cardiac reserve. Mannitol can cause other major adverse reactions including hypernatremia, hyperkalemia, hyperosmolality, circulatory overload, renal failure, allergic reactions, and seizures. Mannitol""s effects on plasma potassium and sodium can produce potentially life-threatening complications in surgical patients with underlying conditions such as cardiac or renal disease, or in patients with preexisting electrolyte abnormalities.
Dopamine is an inotropic agent that stimulates dopaminergic and alpha-adrenergic receptors. Dopamine is sometimes used in surgical settings to improve renal blood flow in an attempt to augment urine flow. Dopamine is also a natriuretic agent; it produces an increase in urine sodium excretion. Adverse effects of dopamine infusion in surgical patients can include hypotension, hypertension, tachycardia, hyponatremia, and cardiac arrhythmias. Dopamine can also cause renal artery vasoconstriction, thereby reducing urinary sodium and water excretion. Dopamine is contraindicated in patients receiving cyclopropane or halothane anesthesia.
There is a continuing, unfilled need for improved diuretic compounds that may be used during surgery or treatment for severe trauma under a general, gaseous anesthetic. There is particularly an unfilled need for diuretic compounds that induce a constant level of urine flow, that protect the kidneys from damage, and that do not cause excessive loss of water or electrolytes. I.e., there is a continuing, unfilled need for diuretic compounds that preserve kidney function while maintaining homeostasis of intravascular volume, electrolyte concentration, and osmolality.
Endogenous opioid receptors have been identified in both the central nervous system (brain and spinal cord), and in the periphery. These receptors have been classified into three major subtypes: mu, delta, and kappa receptors. Morphine and related compounds are often called xe2x80x9cmu opioids,xe2x80x9d because they bind to mu receptors. The so-called xe2x80x9ckappa opioid agonists,xe2x80x9d first discovered about fifteen years ago, bind instead to kappa receptors with high selectivity. A compound is considered a kappa opioid agonist if it binds to kappa receptors in a binding assay, or if it demonstrates kappa agonist activity in functional assays. The kappa agonists are as effective as morphine in relieving pain. But unlike morphine, kappa agonists are not addictive, and do not cause cardiovascular or respiratory depression at the doses required for analgesia.
The kappa opioids, which are unique in being analgesic without being addictive, were initially regarded as a potential breakthrough in the therapeutic management of chronic pain. However, despite substantial research efforts by several pharmaceutical companies over the past fifteen years, no kappa opioid agonists have been approved in any country for any indication to date. The reason is that kappa agonists cause dysphoria that is not well tolerated by patients during chronic use. The sensation of dysphoria differs between individuals, variously including dizziness, fatigue, paresthesia, headache, feeling xe2x80x9chigh,xe2x80x9d thinking abnormally, emotional lability, facial flushing, nausea, and vomiting. Unsuccessful attempts have been made to separate the analgesic and dysphoric properties of kappa agonists.
Early studies of the analgesic effects of kappa opioids recognized a side effect of those compounds, namely that they produced a marked diuretic response in conscious laboratory animals (i.e., they increase urine output). It was also observed that kappa opioids have antinatriuretic properties in conscious laboratory animals (i.e., they cause sodium retention). The diuretic and antinatriuretic properties of kappa opioids have not been the focus of much research because of the dysphoria induced by these compounds. The induced dysphoria effectively precludes any chronic use of a kappa opioid.
Each of the following patents discloses that kappa opioid agonists have various characteristics including diuretic properties: Horwell et al., U.S. Pat. Nos. 4,663,343, 4,906,655, 4,965,278, 5,019,588, 5,063,242; Clemence et al., U.S. Pat. Nos. 4,888,355, 4,988,727; Zimmerman et al., U.S. Pat. Nos. 4,891,379, 4,992,450, 5,064,834, 5,319,087, 5,422,356; Naylor et al., U.S. Pat. No. 5,116,842; Moura et al., U.S. Pat. Nos. 5,068,244, 5,130,329; and McKnight et al., U.S. Pat. Nos. 5,317,028, and 5,369,105.
S. Salas et al., xe2x80x9c[N-Methyl-Tyr1,N-Methyl-Arg7-D-Leu8]-Dynorphin-A-(1-8) Ethylamide, a Stable Dynorphin Analog, Produces Diuresis by Kappa-Opiate Receptor Activation in the Rat,xe2x80x9d J. Pharmacol. Exp. Ther., vol. 262, pp. 979-986 (1992) reported a series of experiments on the effect of E-2078, a kappa opioid agonist, on urine flow in rats. In these experiments, conscious rats were reported to have a basal urine flow rate of 40xc2x17.5 xcexcl/min. After i.v. administration of 50 xcexcg of E-2078, the urine flow rate in the conscious rats increased to 118xc2x122 xcexcl/min after 15-30 minutes, an increase of 78 xcexcl/min over the baseline flow rate. When the study was repeated in rats anesthetized with pentobarbital, a barbiturate (not a gaseous anesthetic), the basal urine flow rate dropped substantially, to 4.0xc2x10.5 xcexcl/min. When 50 xcexcg of E-2078 was administered i.v. to the anesthetized rats, the urine flow rate increased, but only slightly, to 6.3xc2x11.0 xcexcl/min, still well below the basal rate in the conscious animals. Pentobarbital anesthesia dramatically reduced the ability of the kappa agonist to increase urine output. The intravenous (i.v.) administration of 50 xcexcg E-2078 was also reported to decrease urinary sodium excretion from 3.0xc2x10.6 xcexcEq/min (basal) to 1.4xc2x10.4 xcexcEq/min (at 30-45 min) in conscious rats. In pentobarbital-anesthetized rats, basal urinary sodium excretion was reported to drop to 0.2 xcexcEq/min. However, the i.v. administration of 50 xcexcg of E-2078 to the pentobarbital-anesthetized rats did not evoke an antinatriuretic response, but instead caused a slight increase in urinary sodium excretion to 0.3xc2x10.1 xcexcEq/min.
In these experiments of Salas et al., as well as in the reported work of others discussed below, the animals were anesthetized with a barbiturate, and not with an inhaled gaseous anesthetic such as isoflurane, halothane, or nitrous oxide. These two classes of anesthetic agents (barbiturates and gaseous anesthetics) have very different physiological properties. Effects produced by one type of anesthetic cannot be extrapolated to the other. In contemporary surgical practice in humans, barbiturates are used only as presurgical anxiolytic agents or as induction agents, and are not used for maintaining anesthesia during surgery. Gaseous anesthetics are used to maintain anesthesia in humans during surgery.
Barbiturates modulate the action of neurotransmitters at specific receptor sites. For example, it is known that barbiturates bind to xcex3-aminobutyric acid (GABA) receptors, thereby enhancing the inhibitory action of GABA on the central nervous system. By contrast, gaseous anesthetics do not directly bind to specific receptor sites. Instead, gaseous anesthetics act on the lipid matrix of the cell membrane to distort the channels involved in sodium conductance, thereby stabilizing nerve membranes and reducing nerve activity.
Barbiturates are metabolized by liver enzymes to active metabolites. Gaseous anesthetics are eliminated, largely unchanged, through expiration. Barbiturates and gaseous anesthetics have different effects on the release of circulating hormones (e.g., epinephrine, histamine, angiotensin II, vasopressin, aldosterone, adrenocorticotropic hormone). Barbiturates increase renal vascular resistance, while gaseous anesthetics decrease renal vascular resistance. Barbiturates cause central nervous system stimulation and can induce seizures, whereas gaseous anesthetics do not cause seizure activity.
Because barbiturates and gaseous anesthetic agents operate through separate mechanisms, have different effects on neural and hormonal systems, and produce different central and peripheral nervous system responses, results obtained with one type of anesthetic cannot be extrapolated to the other. In particular, barbiturates and gaseous anesthetics use different mechanisms to produce acute renal failure and to decrease urine and electrolyte output during surgery. The same physiological result (e.g. impaired renal function during anesthesia and surgery) therefore does not imply the same cause, nor does it imply a similar mode of treatment.
G. Slizgi et al., xe2x80x9dEffects of the Highly Selective Kappa Opioid, U-50,488, on Renal Function in the Anesthetized Dog,xe2x80x9d J. Pharmacol. Exp. Ther., vol. 230, pp. 641-645 (1984) reported a series of experiments on U-50,488-induced diuresis in dogs. Dogs were anesthetized with sodium pentobarbital, and were administered 0.9% saline at a rate of 0.2 ml/min/kg. Groups of anesthetized dogs were given a single i.v. dose of U-50,488, at one of the following dosages: 0.2, 1, or 5 mg/kg. Despite the high saline infusion rate (0.2 ml/min/kg), control urine flow rates in these groups of dogs before U-50,488 administration only ranged from 0.031xc2x10.007 (in the lowest dose group, 0.2 mg/kg) to 0.063xc2x10.020 ml/min/kg (in the middle dose group, 1 mg/kg). The administration of U-50,488 caused a dose-dependent increase in urine flow rate, peaking within two hours. The lowest dose (0.2 mg/kg) produced about a 2.5-fold increase in urine flow rate (i.e. to approximately 0.078 ml/min/kg). The highest dose (5 mg/kg) produced about a 7-fold increase in urine flow rate (from 0.047 ml/minlkg, estimated basal level from average of range, to approximately 0.329 ml/min/kg). Heroic intravenous doses (e.g. 0.2, 1 and 5 mg/kg) of U-50,488Hxe2x80x94doses that would never be administered to a humanxe2x80x94were necessary to produce these responses in the pentobarbital-anesthetized dogs. That these doses were excessive is illustrated, for example, by G. Peters et al., xe2x80x9cDiuretic Actions in Man of a Selective Kappa Opioid Agonist: U-62,066E,xe2x80x9d J. Pharmacol. Exp. Ther., vol. 240, pp. 128-131 (1987). Peters et al. reported that in conscious humans the intramuscular administration of only 5 xcexcg/kg of the kappa agonist spiradoline (U-62,066E) (which is about twice as potent a diuretic as U-50,488H) evoked a pronounced diuretic response. See also G. Rimoy et al., xe2x80x9cThe Cardiovascular and Central Nervous System Effects in the Human of U-62,066E,xe2x80x9d Eur. J. Clin. Pharmacol, vol. 46, pp. 203-207 (1994), reporting that a 3.2 xcexcg/kg dose of spiradoline caused sedation, significant dysphoria, and no significant euphoria in humans.
D. Brooks et al., xe2x80x9cOpiate Receptors in the Blood-Brain Barrier Mediate Kappa Agonist-Induced Water Diuresis,xe2x80x9d J. Pharmacol. Exp. Ther., vol. 266, pp. 164-171 (1993) reported experiments suggesting that the ability to cross the blood-brain barrier may be important in kappa opioid-induced water diuresis. The underlying motivation was presumably that if kappa opioids could be shown to produce a diuretic response by action solely in the periphery (i.e., by action outside the brain), then new generation kappa opioids that did not enter the brain might be found useful in treating chronic conditions without the complications of central nervous system effects such as analgesia and dysphoria. For example, if new generation kappa agonists could be developed that did not have analgesic/dysphoric properties, but that could still produce a diuretic response, the compounds might be useful as water diuretics for chronic hyponatremic disorders. Conscious rats were infused intravenously with saline at 10 xcexcl/min, and were hydrated by a bolus administration of lukewarm water intragastrically. The effects of kappa opioids on the rats were then studied. When urinary output exceeded the infusion rate by 2 ml, it was replaced by lukewarm tap water via the stomach catheter. Two kappa opioids that cross the blood-brain barrier, and one that does not, were all shown to produce a dose-dependent increase in urine output in conscious rats. The effects of the same kappa opioids were also examined in conscious dogs that were infused intravenously with 0.45% saline containing 2.5% dextrose at 0.05 ml/kg/min. In the conscious dogs, none of the kappa opioids produced a change in urine output, although some central nervous system side effects (e.g., trembling, restlessness) were observed with the kappa opioids that enter the brain. When these studies were repeated in dogs that were lightly anesthetized with pentobarbital, only the kappa opioids that cross the blood-brain barrier produced a diuretic response. Because the peripherally-acting kappa opioid (i.e., the kappa opioid that does not cross the blood-brain barrier) produced a diuretic response in conscious rats, but not in conscious dogs, it was concluded that kappa opioids have different peripheral mechanisms for producing diuretic responses (e.g., different direct actions on the kidneys) in rats and dogs. Conscious humans are probably more similar to dogs in this regard (the peripheral mechanisms that control urine output). The authors thus concluded that it was unlikely that a peripherally-acting, kappa-agonist water diuretic with limited effects on the central nervous system could be successfully developed for chronic use in humans. To the inventor""s knowledge, no such compounds have in fact been developed to date.
In the studies of both Brooks et al. and Slizgi et al., dogs were anesthetized with pentobarbital, which is a barbiturate. As previously discussed, it cannot be inferred that drugs will produce the same responses under conditions of barbiturate anesthesia and gaseous anesthesia, because the two types of anesthetics evoke different physiological responses acting through different mechanisms. Furthermore, the barbiturate pentobarbital is not used in humans to maintain anesthesia during surgery. In the Brooks et al. investigation, dogs were not studied during surgery under general anesthesia. Rather, the dogs were surgically implanted with arterial catheters under anesthesia, and were then allowed three weeks to recover. On the day of the experiments, the effects of kappa opioids were examined in pentobarbital-anesthetized dogs that did not undergo any major invasive surgical operation. The absence of any invasive surgery during the general anesthesia is significant, as it is recognized that it is the combination of anesthesia and the surgical insult that causes impairment of renal function and reduced urine and electrolyte output. See D.R. Bevan et al., xe2x80x9cRenal Function During and After Anaesthesia and Surgery: Significance for Water and Electrolyte Management,xe2x80x9d Brit. J. Anaesth., vol. 45, pp. 968-975 (1973). By contrast, Slizgi et al. studied the renal effects of kappa opioids on pentobarbital-anesthetized dogs on which invasive surgery was performed. Observed urine flow rates were low (as compared to the rates of intravenous saline infusion), and only heroic doses of the kappa agonist were found to produce a significant increase in urine flow rate.
D. Kapusta, xe2x80x9cOpioid Mechanisms Controlling Renal Function,xe2x80x9d Clin. Exp. Pharmacol. Physiol. vol. 22, pp. 891-902 (1995) gives a review of the effect of opioids on renal function.
N. Ashton, xe2x80x9cxcexa-Opioid-Receptor Agonists Modulate the Renal Excretion of Water and Electrolytes in Anaesthetized Rats,xe2x80x9d Br. J. Pharmacol., vol. 99, pp. 181-185 (1990), reported experiments in which rats anesthetized with Inactin (a barbiturate that is not used for maintenance of anesthesia in humans) were loaded intravenously with hypotonic saline at a very high infusion rate (150 xcexcl/min) for three hours. (This water-loading presumably produced non-physiological conditions in the animals.) After three hours of the hypotonic saline loading, the rats received a subcutaneous injection of U-50,488 or tifluadom (a kappa opioid), at the high doses of 10 and 3.5 mg/kg, respectively. Urinary flow for rats given U-50,488 increased from a baseline rate of about 150 xcexcl/min (about equal to the rate of the hypotonic saline infusion), to a peak of about 220 xcexcl/min at 60 minutes after injection. The increased urine flow was not sustained, however, and urine flow dropped below baseline to about 90 xcexcl/min at 200 minutes after injection. Tifluadom produced a similar diuresis.
P. Reece et al., xe2x80x9cDiuretic Effects, Pharmacokinetics, and Safety of a New Centrally Acting Kappa-Opioid Agonist (CI-977) in Humans,xe2x80x9d J. Clin. Pharmacol., vol. 34, pp. 1126-1132 (1994) reported that the intramuscular administration of CI-977, a kappa opioid agonist, increased urine flow in conscious humans. However, negative side effects were reported, including dizziness, fatigue, paresthesia, headache, vasodilation (facial flushing), emotional lability, feeling xe2x80x9chigh,xe2x80x9d and abnormal thinking. The dose of CI-977 ranged from 5 to 25 xcexcg in individuals weighing from 50.5 to 117.9 kg. Reece et al. reported that the diuresis produced by kappa receptor agonists may be mediated by alterations in antidiuretic hormone activity.
G. Peters et al., xe2x80x9cDiuretic Actions in Man of a Selective Kappa Opioid Agonist: U-62,066E,xe2x80x9d J. Pharmacol. Exp. Ther., vol. 240, pp. 128-131 (1987), disclosed that the kappa agonist U-62,066E injected intramuscularly at doses ranging from 2 to 6 xcexcg/kg induced water diuresis in conscious humans, without increases in sodium, potassium, or chloride excretion.
In conscious rats, administration (i.v. bolus or infusion) of kappa opioids produces changes in urine flow similar to those produced by other clinically used diuretics. For example, D. Kapusta et al., xe2x80x9cRole of Renal Nerves in Excretory Responses to Administration of Kappa Agonists in Conscious Spontaneously Hypertensive Rats, xe2x80x9dJ. Pharmacol. Exp. Ther., vol. 251, pp. 230-237 (1989) reported that in conscious rats intravenous infusion of the kappa opioid U-50,488H (20 xcexcg/kg/min) produced a diuretic response that was rapid in onset (10 minutes), of large magnitude (150-200 xcexcg/min increase over baseline, with a peak magnitude at 30-40 minutes) and of relatively short duration (approximately 60-80 minutes).
D. Kapusta et al., xe2x80x9cCentral Kappa Opioid Receptor-Evoked Changes in Renal Function in Conscious Rats: Participation of the Renal Nerves,xe2x80x9d J. Pharmacol. Exp. Ther., vol. 267, pp. 197-204 (1993) reported that in conscious rats administration of U-50,488H into the lateral ventricle of the brain produced a diuretic response that was similar in magnitude and time course to those observed in the other studies reported above. See also D. Kapusta et al., xe2x80x9cCentral Kappa Opioids Blunt the Renal Excretory Responses to Volume Expansion by a Renal Nerve-Dependent Mechanism,xe2x80x9d J. Pharmacol. Exp. Ther., vol. 273, pp. 199-205 (1995).
G. Rimoy et al., xe2x80x9cMechanism of diuretic action of spiradoline (U-62,066E)xe2x80x94a Kappa Opioid Receptor Agonist in the Human,xe2x80x9d Br. J. Clin. Pharmac., vol. 32, pp. 611-615 (1991) reported that the kappa agonist U-62,066E significantly increased urine output and decreased urine osmolality in conscious healthy humans. It was reported that U-62,066E altered neither plasma antidiuretic hormone activity nor renal hemodynamics. Rimoy et al. concluded that a mechanism other than a change in antidiuretic hormone activity or renal hemodynamics was responsible for producing kappa opioid-induced diuretic effects in conscious humans.
It has unexpectedly been discovered that kappa-opioid agonists may be used to prevent the impairment of renal function that occurs during surgery or treatment of severe trauma under gaseous anesthesia. Not only do kappa opioid agonists preserve renal function and maintain a constant level of urine output during anesthesia and surgery, but they also preserve sodium, potassium, calcium, and total osmolality, thereby helping to keep plasma electrolyte levels constant.
The preservation of urine flow while maintaining body sodium, potassium, calcium, and total osmolality levels during surgery or treatment of severe trauma under gaseous anesthesia has never previously been achieved. Kappa agonists may be used in healthy patients, but are particularly useful for surgical patients with compromised cardiovascular or renal function, or otherwise having a prior condition of water or electrolyte imbalance. This invention encompasses the use of kappa opioid agonists to induce diuresis in anesthetized mammals (including humans) during surgery or treatment of severe trauma, where the anesthesia is induced by a volatile, inhaled anesthetic, including one or more of the following: isoflurane, enflurane, desflurane, nitrous oxide, halothane, ethylene, cyclopropane, sevoflurane, and methoxyflurane.
To the inventor""s knowledge, no prior reference has suggested a method for maintaining a constant and adequate output of urine while maintaining homeostasis of blood volume, electrolyte concentration, and osmolality during gaseous anesthesia and surgery or trauma. All known prior diuretic agents that have been used during surgery (e.g., furosemide, ethacrynic acid, mannitol) are known to have significant limitations. For example, after the initial drop in urine flow induced by anesthesia and surgery, the administration of current, clinically-used diuretics evokes a characteristic spike increase in urine flowxe2x80x94sometimes to undesirably high levelsxe2x80x94followed by a rebound shutdown of urine output. The fluctuations in urine output associated with the use of prior diuretics cause an increase, then a decrease, and then another increase in intravascular volume (i.e., hypervolemia, hypovolemia, and hypervolemia, respectively). Large fluctuations in plasma electrolyte concentration and osmolality often result as well. In addition, prior diuretics can be ineffective in modifying urine output in surgical patients with certain pre-existing conditions (e.g., cirrhosis with ascites, congestive heart failure, or chronic renal failure, or hypotension following severe traumatic injury or shock).
Although it was previously known that kappa opioids produce a diuretic response in conscious animals, it was nevertheless surprising to find that these compounds were effective in controlling the adverse effects of gaseous anesthesia on kidney function during surgery or trauma. The onset, magnitude, and duration of the effects of kappa opioid pretreatment on anesthetized rats during surgery were significantly different from the effects on conscious animals. In addition, the required dose is substantially different in conscious and anesthetized animals. The dose of kappa agonist that produced the maximal diuretic response in a conscious animal did not prevent or reverse the impaired renal function induced by surgery and isoflurane anesthesia. By sheer chance it was discovered that by substantially increasing the dose of a kappa agonist, and by controlling the timing of its administration, a qualitatively different response can be produced during surgery or treatment of severe trauma under gaseous anesthesia. In particular, a four-fold higher dose of kappa agonist than will induce diuresis in a conscious animal was found to be effective in completely preventing the surgery and gaseous anesthetic-induced impairment of kidney function; it was also found that the kappa agonist was most effective only when administered as a pretreatment while the animal was in conscious state, during a period of time prior to the start of anesthesia and surgery. No prior reference has suggested these effects.
For example, intravenous infusion (55 xcexcl/min) of conscious rats with 25 xcexcg/kg/min of U-50,488H produced a marked diuresis, but the same dose was completely ineffective as a diuretic in rats during surgery and isoflurane anesthesia. However, when rats were first pretreated with a four-fold larger dose of U-50,488H (100 xcexcg/kg/min) while conscious for 15 minutes, and were then anesthetized (induced with thiopental and maintained with isoflurane) and operated upon, the characteristic changes in urine output caused by kappa agonists in conscious animals did not occur (i.e., there was not a profound diuretic response and then a compensatory antidiuretic response). Instead, urine flow rate remained constant during infusion of U-50,488H (60 minutes) at approximately 50-70 xcexcl/min, a level similar to that observed before administration of anesthesia and surgery. After stopping the infusion of U-50,488H, the urine flow rate remained elevated at a similar level for an additional 100-120 minutes.
These findings are the first to demonstrate a method by which urine output may be preserved during surgery or treatment of severe trauma under gaseous anesthesia without undesirable levels of electrolyte loss. This unique combination of activities is highly desirable during surgery or treatment of severe trauma. Because the action of kappa opioids in maintaining kidney function during surgery appears to be independent of blood pressure, these agents may be particularly useful in surgical patients, and in patients suffering from a severe traumatic injury in which renal perfusion pressure is reduced (e.g., those suffering from shock, hypotension, or renal failure). That the kappa opioids act independent of changes in blood pressure was shown in observations that urine output remained elevated and constant in rats during continuous kappa opioid infusion, despite a reduction in blood pressure to approximately 75-80 mm Hg resulting from long-term isoflurane anesthesia, or resulting from enhancing the level of isoflurane anesthesia. In other observations, it was found that while urine output remained elevated and constant, the reduction in blood pressure resulting from kappa agonist infusion during long-term isoflurane anesthesia was prevented by reducing the inhaled concentration of isoflurane.
Because this novel use for kappa opioid agonists is acute (i.e., for a period of hours) rather than chronic (i.e., for a period of days, weeks, months, or years), the possibility of short-lived dysphoria is an acceptable side effect. P. Reece et al. (1994) reported that the time to onset of adverse effects was normally 15 to 30 minutes post-dose for the kappa opioid CI-977, and that the adverse effects persisted up to 4 hours after intramuscular injection. To prevent the anesthesia-and-surgery-induced impairment of renal function, continuous administration of a kappa agonist preferably begins about 15 to 30 minutes before induction and maintenance of anesthesia and the start of surgery. If the kappa agonist is administered too long before the induction and maintenance of anesthesia (more than about 45-40 minutes before), then an antidiuretic compensatory effect can commence before anesthesia is induced. This compensatory effect can continue during anesthesia, and can block the diuretic effect that the kappa agonist would otherwise exert during anesthesia and surgery.
While a one-time, short-lived dysphoric response to this kappa opioid pretreatment is possible, this potential adverse response is likely to be masked by the actions of other drugs or the anesthetic agent. For instance, drugs such as diazepam (Valium), morphine, meperidine (Demerol), codeine, oxycodone, etc., are typically used as pre-, peri-, and post-operative medications in the surgical patient, and should conceal any dysphoria otherwise resulting from the kappa opioid. By contrast, persistent dysphoric effects make intolerable the chronic administration of kappa opioids for other uses.